This invention relates to a carbon dioxide indicator device and more particularly to a carbon dioxide indicator device of the kind which comprises a chemically inert substrate and an indicator composition supported by the substrate and responsive to exposure to carbon dioxide in expired respiratory air to undergo a colour changing reaction, said indicator composition including a pH sensitive dye and a basic substance selected from the group consisting of quaternary ammonium and phosphonium salts.
Colorimetric carbon dioxide indicator devices of this kind are used to detect the presence of a certain minimum content of carbon dioxide in the air expired by a human being. When the indicator devices are used, the carbon dioxide reacts with the indicator composition to change the pH of the environment in which the pH sensitive dye operates and thereby cause a colour change in the indicator composition.
For example, they can be used to verify that a patient has been correctly intubated, that is, that a tracheal tube has been properly placed in the trachea instead of in the oesophagus. If the tracheal tube has been properly placed, the air expired by the patient through the tracheal tube contains carbon dioxide in an amount that is significantly higher than that of air in the oesophagus; the air in the trachea normally contains 5-6 percent carbon dioxide, whereas the air in the oesophagus normally only contains about 0.03 percent carbon dioxide. A calorimetric carbon dioxide indicator device of the kind mentioned above may be placed inside a transparent portion of the tracheal tube proper or some other device passing the expired air such that the expired air contacts the indicator composition and causes it to change colour, thereby providing a visual indication of the presence of carbon dioxide in the expired air.
In the above-mentioned use, as well as in some other uses, a qualitative detection of carbon dioxide is adequate, so that it suffices that the indicator composition undergoes sufficiently distinct reversible changes of colour rapidly enough to enable an anesthesiologist, for example, to observe the fluctuations of the carbon dioxide content that occur during the inspirations and expirations of the patient. See, for example, U.S. Pat. No. 5,005,572 (Raemer et al), which teaches use of, among other substances, quaternary ammonium or phosphonium salts as part of the indicator composition. These quaternary ammonium and phosphonium salts have the following general formula 
in which
X is a nitrogen or phosphorus atom,
each of R1, R2, R3 and R4 is an alkyl,
Yxe2x88x92 is an anion selected from the group consisting of hydroxide, fluoride, chloride, bromide, iodide, carbonate, and tetrafluoroborate.
More specifically, in these prior art indicator compositions each of the alkyls R1, R2, R3 and R4 have from 1 to 12 carbon atoms.
A recently disclosed compact and inexpensive colorimetric carbon dioxide analyzer suitable for quantitative applications in which, for cost or other reasons, IR-analyzers are unsuited, makes use of a carbon dioxide indicator device of the kind mentioned above, see Anesthesiology, Volume 85, No. 3, Abstract 440 (September 1996).
However, the usefulness of this analyzer is limited by problems inherent in the properties of the carbon dioxide indicator devices now available, notably the response time of the indicator compositions. The time it takes for the indicator composition to undergo a more or less complete change in its colour in response to a sudden exposure to carbon dioxide should be shorter than the duration of the expiration phase of a single breath, i.e. shorter than about half the duration of a single breath. It is desirable for the indicator composition to respond sufficiently rapidly to enable photoelectric calorimetric monitoring of the carbon dioxide variation throughout the expiration phase with an accuracy that is comparable to that which can be achieved with an IR analyzer.
A healthy adult typically breathes at a rate of about 15 breaths per minute at rest so that the duration TE of the expiration phase then is about 2 seconds, a variation of TE within the range of 1.5 to 4 seconds being normal. For children and neonates, the corresponding range is 0.75 to 1.5 seconds and 0.5 to 1 second, respectively.
The response time of prior art carbon dioxide indicator compositions of the kind indicated above is greatly dependent on the humidity of the environment in which the indicator composition operates. Unfortunately, the expired air is saturated with water while the inspired air may be relatively dry. In order that the carbon dioxide indicator composition may provide consistent quantitative indications even when the duration of the expiratory phase is short, say 2 seconds or less, it should therefore be substantially insensitive to the humidity of the environment in which it operates.
It has been proposed to provide for a fast response by incorporating a plasticiser in the carbon dioxide indicator compositions, see U.S. Pat. No. 5,472,668 (Mills et al). However, the incorporation of a plasticiser reduces the shelf life of the indicator devices to a few months, thereby making the indicator devices unsuited for use in commercial instruments.
Replacing plasticisers with other water insoluble substances may resolve the shelf life problem (see WO96/24054) but will not shorten the response time sufficiently to permit an accurate quantitative monitoring of the carbon dioxide variations during the individual expiration phases.
An object of the present invention is to provide a fast-response calorimetric carbon dioxide indicator device of the kind mentioned initially which is substantially insensitive to humidity variations within the range encountered in its use for indicating carbon dioxide in expired air and the shelf life of which is sufficiently long to enable it to be used in commercial carbon dioxide analyzers.
In the pursuit of such a calorimetric indicator device it has surprisingly been found that indicator compositions, the basic substance of which corresponds to the following general formula (1) and in which at least one of the alkyls R1, R2, R3 and R4 has at least 13 carbon atoms and at least one of the other alkyls has from 6 to 8 carbon atoms, the remaining alkyls, if any, having from 1 to 12 carbon atoms, perform very well in respect of the above-mentioned requirements.
In accordance with this finding, the above-stated object of the invention is achieved with a fast-response calorimetric carbon dioxide indicator device which is substantially insensitive to humidity and comprises a chemically inert substrate and an indicator composition supported by the substrate and responsive to exposure to carbon dioxide in expired respiratory air to undergo a colour changing reaction, said indicator composition including a pH sensitive dye and a basic substance having the general formula 
in which
X is a nitrogen or phosphorus atom,
each of R1, R2, R3 and R4 is an alkyl,
Yxe2x88x92 is an anion selected from the group consisting of hydroxide) fluoride, chloride, bromide, iodide, carbonate, and tetrafluoroborate,
at least one of the alkyls R1, R2, R3 and R4 having at least 13 carbon atoms and at least one of the other alkyls having from 6 to 8 carbon atoms, the remaining alkyls, if any, having from 1 to 12 carbon atoms.
If only one of the alkyls has more than 12 carbon atoms and only one has from 6 to 8 carbon atoms, the other two alkyls are similar or dissimilar to the numbers of carbon atoms being within the range from 1 to 12.
The term alkyl as used in this description and in the claims encompasses both linear and branched alkyls.
In a preferred embodiment of the indicator device according to the invention, R1 is tetradecyl and thus has 14 carbon atoms and each of R2, R3 and R4 is hexyl and thus has 6 carbon atoms.
As in the prior art carbon dioxide indicator, the indicator composition may be provided as a coating on a suitable backing, such as a polymeric sheet, preferably transparent so that the coating can be viewed through it. The coating may also be covered by a protective gas-permeable membrane of a suitable material allowing gaseous carbon dioxide to pass freely through it but blocking passage of liquids.
The dye forming part of the indicator composition may be any of the many different dyes which are conventional in colorimetric carbon dioxide indicators of the kind with which the invention is concerned, such as thymol blue.
For a proper understanding of the present invention it is important to note that the shorter the carbon chains of the alkyls of the basic substance included in the indicator composition according to the invention, the more hydrophilic and water soluble the basic substance. If the carbon chains have more than about 8 carbon atoms, the basic substance is substantially water insoluble and hydrophobic.
However, a certain amount of molecular water has to be present in the indicator composition, because the colour changing reaction requires the carbon dioxide to combine with molecular water. If all four carbon chains contain more than 10-12 carbon atoms, the amount of water present will be insufficient for the colour changing reaction to take place properly, even when the air contacting the indicator composition is humid. If the air is dry, even indicator compositions in which the carbon chains are shorter fail to respond properly to exposure to carbon dioxide. For example, when all carbon chains have 8 atoms and a hydrophilic substance is not incorporated in the indicator device, no reliable quantitative indication of carbon dioxide is possible if the gas containing the carbon dioxide has a relative humidity below about 20% (A Gedeon, P Krill and C Mebius, Anesthesia 49, 798-103, 1994).
If, on the other hand, the indicator composition is too hydrophilic, because the number of carbon atoms of the carbon chains is much smaller than 8 and/or because the indicator composition includes a strongly hydrophilic substance, the indicator composition will respond very slowly to carbon dioxide. Particularly in the humid environment in which the indicator device operates in clinical use, the response will be useless for accurate capnographic recording, as will be shown below.